A distributed network of regions, both cortical (e.g., prefrontal cortex, anterior cingulate cortex, insular cortex) and subcortical (e.g., amygdala, thalamus, ventral striatum), increase their synaptic activity during the presentation of emotional stimuli or the experience of emotional states. Functional and structural changes in some of these regions have also been implicated in the pathophysiology of mood disorders (e.g., Major Depression). By comparison, relatively little information has been acquired on the neurotransmitter systems involved in the regulation of emotional and mood states in humans, and by extension, in Borderline Personality Disorder (BPD). There are suggestions that the endogenous opioid system (EOS) may have physiological relevance to some BPD symptoms such as stress-related analgesia, dissociative behavior, and self-injurious activity. Recent work from our laboratory has also implicated the EOS in affective regulation during the experience of negative emotional states, as well as in response to stressors. The EOS may therefore interface sensory-related symptoms of BPD with abnormalities in affective regulation present in this disorder. The utilization of radiotracers labeling specific receptor sites and appropriate kinetic models allows the examination of neurotransmitter release in response to experimental challenges. Employing these techniques, we have demonstrated the involvement of mu-opioid-receptor mediated opioid neurotransmission in the regulation of stress and affective responses, as well as sex and genetic influences on these phenomena. The present proposal extends this work to BPD patient volunteers and age- and sex-matched healthy controls. The additional influence of chronic stress on interindividual variations in these responses is also introduced. Secondary analyses will be performed to preliminarily examine the contribution of met158val COMT genotypes to these interindividual variations. The psychophysiological consequences of these genotypic and endophenotypic influences will then be examined using both objective (e.g., HPA axis measures) and subjective measures (e.g., ratings of pain, affective states, mood). The results obtained in these studies will provide a foundation for a systems-level understanding of neurochemical and behavioral responses to a stressor in BPD, and the circuits and regulatory mechanisms critically involved in this disorder. This information is critical for the understanding of the biological mechanisms underlying the symptomatology of BPD, and to guide future research and treatment interventions in this common but poorly understood illness.